Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes.

Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft.

Unpacking and validating the "physiological adaptation" core concept of physiology.

A national Task Force of 25 Australian physiology educators used the Delphi protocol to develop seven physiology core concepts that were agreed to nationally. The aim of the current study was to unpack the "physiological adaptation" core concept with the descriptor "organisms adjust and adapt to acute and chronic changes in the internal and external environments across the lifespan." This core concept was unpacked by three Task Force members and a facilitator into four themes and nine subthemes that encompass the role of stressors and disturbed homeostasis in adaptation and the capacity for, and the nature of, the physiological adaptation. Twenty-two Task Force members then provided feedback and rated the themes and subthemes for level of importance and difficulty for students to learn via an online survey using a five-point Likert scale. Seventeen respondents completed all survey questions. For all themes/subthemes, importance was typically rated 1 (Essential) or 2 (Important) (n = 17, means ±SD ranged from 1.1 ± 0.3 to 2.2 ± 0.9), and difficulty was typically rated 3 (Moderately Difficult) (n = 17, means ranged from 2.9 ± 0.7 to 3.4 ± 0.9). Subtle differences in the proportion of importance scores (n = 17, Fisher's exact: P = 0.004, ANOVA: F12,220 = 2.630, P = 0.003; n = 22, Fisher's exact: P = 0.002, ANOVA: F12,281 = 2.743, P < 0.001), but not difficulty scores, were observed between themes/subthemes, and free-text feedback was minor. The results suggest successful unpacking of the physiological adaptation core concept. The themes and subthemes can inform the design of learning outcomes, assessment, and teaching and learning activities that have commonality and consistency across curricula.NEW & NOTEWORTHY An Australian Task Force of physiology educators identified physiological adaptation as a core concept of physiology. It was subsequently unpacked into four themes and nine subthemes. These were rated, by the Task Force, Essential or Important and Moderately Difficult for students to learn. The themes and subthemes can inform the design of learning outcomes, assessments, and teaching and learning activities that have commonality and consistency across curricula.

Establishing consensus for the core concepts of physiology in the Australian higher education context using the Delphi method.

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process (n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking.NEW & NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.

Inhibition of HIV-1 Gag-membrane interactions by specific RNAs.

HIV-1 particle assembly, which occurs at the plasma membrane (PM) of cells, is driven by the viral polyprotein Gag. Gag recognizes phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2], a PM-specific phospholipid, via the highly basic region (HBR) in its N-terminal matrix (MA) domain. The HBR is also known to bind to RNA. We have previously shown, using an in vitro liposome binding assay, that RNA inhibits Gag binding to membranes that lack PI(4,5)P2 If this RNA block is removed by RNase treatment, Gag can bind nonspecifically to other negatively charged membranes. In an effort to identify the RNA species that confer this inhibition of Gag membrane binding, we have tested the impact of purified RNAs on Gag interactions with negatively charged liposomes lacking PI(4,5)P2 We found that some tRNA species and RNAs containing stem-loop 1 of the psi region in the 5' untranslated region of the HIV-1 genome impose inhibition of Gag binding to membranes lacking PI(4,5)P2 In contrast, a specific subset of tRNAs, as well as an RNA sequence previously selected in vitro for MA binding, failed to suppress Gag-membrane interactions. Furthermore, switching the identity of charged residues in the HBR did not diminish the susceptibility of Gag-liposome binding for each of the RNAs tested, while deletion of most of the NC domain abrogates the inhibition of membrane binding mediated by the RNAs that are inhibitory to WT Gag-liposome binding. These results support a model in which NC facilitates binding of RNA to MA and thereby promotes RNA-based inhibition of Gag-membrane binding.

Upper limb function in children with attention-deficit/hyperactivity disorder (ADHD).

Upper limb function was investigated in children with ADHD using objective methods. We hypothesised that children with ADHD exhibit abnormal dexterity, force application during manipulation of a novel object, and movement rhythmicity. Two groups of age- and gender-matched children were investigated: 35 typically developing children (controls, 10.5 ± 0.4 years, 32M-3F) and 29 children (11.5 ± 0.5 years, 27M-2F) with formally diagnosed ADHD according to DSM-IV-TR criteria. Participants underwent a series of screening tests and tests of upper limb function while "off" medication. Objective quantification of upper limb function involved measurement of force during a grip and lift task, maximal finger tapping task, and maximal pinch grip. Acceleration at the index finger was also measured during rest, flexion and extension, and a postural task to quantify tremor. The Movement Assessment Battery for Children-2 (MABC-2) was also administered. Significant between-group differences were observed in movement rhythmicity, manipulation of a novel object, and performance of the MABC-2 dexterity and aiming and catching components. Children with ADHD lifted a novel object using a lower grip force (P = 0.036), and held the object with a more variable grip force (P = 0.003), than controls. Rhythmicity of finger tapping (P = 0.008) and performance on the dexterity (P = 0.007) and aiming and catching (P = 0.042) components of the MABC-2 were also significantly poorer in the ADHD group than controls. Movement speed, maximum pinch grip strength, and tremor were unaffected. The results of the study show for the first time that ADHD is associated with deficits in multiple, but not all domains of upper limb function.

History of Illicit Stimulant Use Is Not Associated with Long-Lasting Changes in Learning of Fine Motor Skills in Humans.

Little is known about the long-lasting effect of use of illicit stimulant drugs on learning of new motor skills. We hypothesised that abstinent individuals with a history of primarily methamphetamine and ecstasy use would exhibit normal learning of a visuomotor tracking task compared to controls. The study involved three groups: abstinent stimulant users (n = 21; 27 ± 6 yrs) and two gender-matched control groups comprising nondrug users (n = 16; 22 ± 4 yrs) and cannabis users (n = 16; 23 ± 5 yrs). Motor learning was assessed with a three-minute visuomotor tracking task. Subjects were instructed to follow a moving target on a computer screen with movement of the index finger. Metacarpophalangeal joint angle and first dorsal interosseous electromyographic activity were recorded. Pattern matching was assessed by cross-correlation of the joint angle and target traces. Distance from the target (tracking error) was also calculated. Motor learning was evident in the visuomotor task. Pattern matching improved over time (cross-correlation coefficient) and tracking error decreased. However, task performance did not differ between the groups. The results suggest that learning of a new fine visuomotor skill is unchanged in individuals with a history of illicit stimulant use.

Secondary structure of bacteriophage T4 gene 60 mRNA: implications for translational bypassing.

Translational bypassing is a unique phenomenon of bacteriophage T4 gene 60 mRNA wherein the bacterial ribosome produces a single polypeptide chain from a discontinuous open reading frame (ORF). Upon reaching the 50-nucleotide untranslated region, or coding gap, the ribosome either dissociates or bypasses the interruption to continue translating the remainder of the ORF, generating a subunit of a type II DNA topoisomerase. Mutational and computational analyses have suggested that a compact structure, including a stable hairpin, forms in the coding gap to induce bypassing, yet direct evidence is lacking. Here we have probed the secondary structure of gene 60 mRNA with both Tb³âº ions and the selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) reagent 1M7 under conditions where bypassing is observed. The resulting experimentally informed secondary structure models strongly support the presence of the predicted coding gap hairpin and highlight the benefits of using Tb³âº as a second, complementary probing reagent. Contrary to several previously proposed models, however, the rest of the coding gap is highly reactive with both probing reagents, suggesting that it forms only a short stem-loop. Mutational analyses coupled with functional assays reveal that two possible base-pairings of the coding gap with other regions of the mRNA are not required for bypassing. Such structural autonomy of the coding gap is consistent with its recently discovered role as a mobile genetic element inserted into gene 60 mRNA to inhibit cleavage by homing endonuclease MobA.

Evidence in support of RNA-mediated inhibition of phosphatidylserine-dependent HIV-1 Gag membrane binding in cells.

The matrix domain promotes plasma-membrane-specific binding of HIV-1 Gag through interaction with an acidic lipid phosphatidylinositol-(4,5)-bisphosphate. In in vitro systems, matrix-bound RNA suppresses Gag interactions with phosphatidylserine, an acidic lipid prevalent in various cytoplasmic membranes, thereby enhancing the lipid specificity of the matrix domain. Here we provide in vitro and cell-based evidence supporting the idea that this RNA-mediated suppression occurs in cells and hence is a physiologically relevant mechanism that prevents Gag from binding promiscuously to phosphatidylserine-containing membranes.

Hand function is impaired in healthy older adults at risk of Parkinson's disease.

Abnormal substantia nigra morphology in healthy individuals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson's disease. However, little is known about the functional consequences of this abnormality (termed 'hyperechogenicity') on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN+) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN+ subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN+ aged 58 ± 8 years, 18 SN- aged 57 ± 6 years) were asked to grip and lift a light-weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN+ subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration; 0.27 ± 0.25 s) than SN- subjects (0.13 ± 0.08 s; P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 ± 0.42 N vs. -0.21 ± 0.12 N; P = 0.005) and used a greater grip force to lift the object (19.5 ± 7.0 N vs. 14.0 ± 4.3 N; P = 0.022) than SN- subjects. No between group differences were observed in subsequent trials. SN+ subjects exhibit impaired planning for manipulation of new objects. SN+ individuals over-estimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN+ subjects shares similarities with de novo Parkinson's disease patients.

Clinical Course, Antifungal Susceptibility, and Genomic Sequencing of Trichophyton indotineae.

Importance: Trichophyton indotineae is an emerging dermatophyte causing outbreaks of extensive tinea infections often unresponsive to terbinafine. This species has been detected worldwide and in multiple US states, yet detailed US data on infections with T indotineae are sparse and could improve treatment practices and medical understanding of transmission. Objective: To correlate clinical features of T indotineae infections with in vitro antifungal susceptibility testing results, squalene epoxidase gene sequence variations, and isolate relatedness using whole-genome sequencing. Design, Setting, and Participants: This retrospective cohort study of patients with T indotineae infections in New York City spanned May 2022 to May 2023. Patients with confirmed T indotineae infections were recruited from 6 New York City medical centers. Main Outcome and Measure: Improvement or resolution at the last follow-up assessment. Results: Among 11 patients with T indotineae (6 male and 5 female patients; median [range] age, 39 [10-65] years), 2 were pregnant; 1 had lymphoma; and the remainder were immunocompetent. Nine patients reported previous travel to Bangladesh. All had widespread lesions with variable scale and inflammation, topical antifungal monotherapy failure, and diagnostic delays (range, 3-42 months). Terbinafine treatment failed in 7 patients at standard doses (250 mg daily) for prolonged duration; these patients also had isolates with amino acid substitutions at positions 393 (L393S) or 397 (F397L) in squalene epoxidase that correlated with elevated terbinafine minimum inhibitory concentrations of 0.5 µg/mL or higher. Patients who were treated with fluconazole and griseofulvin improved in 2 of 4 and 2 of 5 instances, respectively, without correlation between outcomes and antifungal minimum inhibitory concentrations. Furthermore, 5 of 7 patients treated with itraconazole cleared or had improvement at the last follow-up, and 2 of 7 were lost to follow-up or stopped treatment. Based on whole-genome sequencing analysis, US isolates formed a cluster distinct from Indian isolates. Conclusion and Relevance: The results of this case series suggest that disease severity, diagnostic delays, and lack of response to typically used doses and durations of antifungals for tinea were common in this primarily immunocompetent patient cohort with T indotineae, consistent with published data. Itraconazole was generally effective, and the acquisition of infection was likely in Bangladesh.

rTMS over human motor cortex can modulate tremor during movement.

Abnormally large tremor during movement is a symptom of many movement disorders and significantly impairs activities of daily living. The aim of this study was to investigate whether repetitive magnetic brain stimulation (rTMS) can reduce tremor size during human movement. We hypothesised that inhibitory rTMS over motor cortex would reduce tremor size during subsequent movement. The study involved 26 healthy young adults (21 ± 2 years) and began with application of single TMS stimuli to measure baseline corticospinal excitability. The response to stimulation was recorded in hand muscles with electromyography. Subjects then performed a 3-min task to measure baseline tremor during movement. This involved matching index finger position with a moving target on a computer screen. Tremor was recorded with an accelerometer on the fingernail. Finger acceleration was analysed with fast-Fourier transform to quantify tremor in the physiological range (7.8-12.2 Hz). Subjects then received 10 min of real (n = 13) or sham (n = 13) inhibitory rTMS. Tremor and corticospinal excitability were then remeasured. Real rTMS significantly decreased corticospinal excitability by ~30% (P = 0.022) and increased tremor size during movement by ~120% (P = 0.047) relative to sham rTMS. However, the direction of tremor change was opposite to that hypothesised for inhibitory rTMS. The results suggest that rTMS over human motor cortex can modulate action tremor and the level of corticospinal excitability may be important for setting the amplitude of action tremor in healthy young adults.

Abnormal maximal finger tapping in abstinent cannabis users.

OBJECTIVE: To investigate movement speed and rhythmicity in abstinent cannabis users, we hypothesized that abstinent cannabis users exhibit decreased maximal finger tapping frequency and increased variability of tapping compared with non-drug users. METHODS: The study involved 10 healthy adult cannabis users and 10 age-matched and gender-matched controls with no history of illicit drug use. Subjects underwent a series of screening tests prior to participation. Subjects were then asked to tap a strain gauge as fast as possible with the index finger of their dominant hand (duration 5 s). RESULTS: The average intertap interval did not significantly differ between groups, but the coefficient of variation of the intertap interval was significantly greater in the cannabis group than in controls (p=0.011). The cannabis group also exhibited a slow tapping frequency at the beginning of the task. CONCLUSIONS: Rhythmicity of finger tapping is abnormal in individuals with a history of cannabis use. The abnormality appears to be long lasting and adds to the list of functional changes present in abstinent cannabis users.

Simple quantitative planimetric measurement of nigrosome-1 for clinical settings.

INTRODUCTION: Loss of MRI hyperintense signal in nigrosome-1 (assessed with susceptibility-weighted imaging) is a biomarker for Parkinson's disease (PD). Current clinical practice involves subjectively rating the appearance of nigrosome-1 which is challenging. The study aimed to test and compare a simple method for quantifying nigrosome-1 with the current subjective rating method. METHODS: Two experienced neuroradiologists measured area of hyperintense signal in nigrosome-1 (quantitative method) and rated nigrosome-1 appearance (as normal, attenuated, or absent; subjective method) in 42 patients encompassing the full spectrum of nigrosome-1 integrity (21 patients aged 55.5 ± 20.9 years with Essential tremor (ET) and a subset of 21 patients aged 69.6 ± 8.6 years with PD). Neuroradiologists were blinded to each other's measurements, clinical notes, and patient group. RESULTS: Both methods yielded a significant difference between the groups (PD vs ET; p < 0.001). Pooled (across sides) area of nigrosome-1 hyperintense signal was significantly smaller in the PD group (median = 2.1 mm2, range = 0-15.8 mm2) than ET group (median = 8.3 mm2, range = 0-15.7 mm2; p < 0.001). Inter-rater reliability was high to very high for both methods (subjective: weighted kappa = 0.640, p < 0.001; quantitative: W = 0.733, p = 0.004). Our primary hypothesis that area of nigrosome-1 hyperintense signal exhibits higher inter-rater reliability than subjective rating of nigrosome-1 appearance was not supported. CONCLUSION: The simple quantitative method, used with subjectively rated nigrosome-1 appearance, may improve confidence in longitudinal clinical reporting, when nigrosome-1 is attenuated. However, further work on the incremental diagnostic value of planimetry and bias, repeatability and reproducibility are needed before it can be recommended in clinical practice.

Neuronal glutamate transporters control reciprocal inhibition and gain modulation in D1 medium spiny neurons.

Understanding the function of glutamate transporters has broad implications for explaining how neurons integrate information and relay it through complex neuronal circuits. Most of what is currently known about glutamate transporters, specifically their ability to maintain glutamate homeostasis and limit glutamate diffusion away from the synaptic cleft, is based on studies of glial glutamate transporters. By contrast, little is known about the functional implications of neuronal glutamate transporters. The neuronal glutamate transporter EAAC1 is widely expressed throughout the brain, particularly in the striatum, the primary input nucleus of the basal ganglia, a region implicated with movement execution and reward. Here, we show that EAAC1 limits synaptic excitation onto a population of striatal medium spiny neurons identified for their expression of D1 dopamine receptors (D1-MSNs). In these cells, EAAC1 also contributes to strengthen lateral inhibition from other D1-MSNs. Together, these effects contribute to reduce the gain of the input-output relationship and increase the offset at increasing levels of synaptic inhibition in D1-MSNs. By reducing the sensitivity and dynamic range of action potential firing in D1-MSNs, EAAC1 limits the propensity of mice to rapidly switch between behaviors associated with different reward probabilities. Together, these findings shed light on some important molecular and cellular mechanisms implicated with behavior flexibility in mice.

Training in a ballistic task but not a visuomotor task increases responses to stimulation of human corticospinal axons.

Short periods of training in motor tasks can increase motor cortical excitability. This study investigated whether changes also occur at a subcortical level. Subjects trained in ballistic finger abduction or visuomotor tracking. The right index finger rotated around the metacarpophalangeal (MCP) joint in a splint. Surface EMG was recorded from the first dorsal interosseous. Transcranial magnetic stimulation over the back of the head (double-cone coil) elicited cervicomedullary motor evoked potentials (CMEPs) by stimulation of corticospinal axons. Responses were recorded from the relaxed muscle before, between, and after two sets of training. In study 1 (n = 7), training comprised two sets of 150 maximal finger abductions. Feedback of acceleration was provided. With training, acceleration increased significantly. CMEPs increased to 248 ± 152% (± SD) of baseline immediately after training (P = 0.007) but returned to control level (155 ± 141%) 10 min later. In study 2 (n = 7), subjects matched MCP joint angle to a target path on a computer screen. After ∼30 min of training, tracking improved as shown by increased correlation between joint angle and the target pathway, reduced time lag, and reduced EMG(rms). However, CMEPs remained unchanged. These results show that transmission through the corticospinal pathway at a spinal level increased after repeated ballistic movements but not after training in a visuomotor task. Thus, changes at a spinal level may contribute to improved performance in some motor tasks.

Corticomotor excitability and plasticity following complex visuomotor training in young and old adults.

Previous studies with transcranial magnetic stimulation (TMS) have shown that advancing age may influence plasticity induction in human motor cortex (M1), but these changes have been assessed with TMS-induced paradigms or simple motor tasks. The aim of this study was to examine changes in corticospinal excitability and intracortical inhibition as markers of corticomotor plasticity following complex motor training in young and old adults. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 16 young (20-35 years) and 16 older (aged 60-75 years) adults before and after motor skill training. Motor training consisted of three 6-minute blocks of a complex visuomotor task that required matching the metacarpophalangeal (MCP) joint angle of the index finger using abduction-adduction movements. Single- and paired-pulse TMS over the left M1 was used to assess changes in right FDI motor-evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) before and after each training block. Visuomotor tracking performance was diminished in old compared with young adults throughout training. However, improvement in tracking error was similar for young and old adults (7-24% increase in each training block). For young and old adults, motor training increased FDI MEP amplitude (≥ 20%) and reduced the magnitude of SICI (≥ 19%) after each visuomotor training block, reflecting use-dependent plasticity. However, no difference in corticomotor plasticity (change in MEP or SICI) was observed between young and old adults. Further studies are needed to identify the experimental or behavioral factors that might contribute to the maintenance of corticomotor plasticity in older adults.

Measurement of the adult human midbrain with transcranial ultrasound.

BACKGROUND: Transcranial sonography is increasingly used to aid clinical diagnoses of movement disorders, for example, to identify an enlarged area of substantia nigra echogenicity in patients with Parkinson's disease. OBJECTIVE: The current study investigated characteristics of the midbrain at the anatomical plane for quantification of substantia nigra echogenicity. METHODS: Area of substantia nigra echogenicity, cross-sectional area of the midbrain, and interpeduncular angle were quantified in two groups of adults aged 18-50 years: 47 healthy non-drug-using controls (control group) and 22 individuals with a history of methamphetamine use (methamphetamine group), a cohort with a high prevalence of enlarged substantia nigra echogenicity and thus risk of Parkinson's disease. RESULTS: In the control group, cross-sectional area of the midbrain (4.47±0.44 cm2) and interpeduncular angle were unaffected by age, sex, or image acquisition side. In the methamphetamine group, cross-sectional midbrain area (4.72±0.60 cm2) and area of substantia nigra echogenicity were enlarged compared to the control group, and the enlargement was sex-dependent (larger in males than females). Whole midbrain area and interpeduncular angle were found to be weak predictors of area of substantia nigra echogenicity after accounting for group and sex. CONCLUSIONS: History of methamphetamine use is associated with an enlarged midbrain and area of substantia nigra echogenicity, and the abnormality is more pronounced in males than females. Thus, males may be more susceptible to methamphetamine-induced changes to the brainstem, and risk of Parkinson's disease, than females.

Adults with a history of recreational cannabis use have altered speech production.

Stereotypical depictions of speech in cannabis users often suggest slow, laboured output, yet objective evidence supporting this assumption is extremely limited. We know that depressants or hallucinogenic drugs such as cannabis can cause acute changes in communication and speech rate, but the long-lasting effects of cannabis use on speech are not well described. The aim of this study was to investigate speech in individuals with a history of recreational cannabis use compared to non-drug-using healthy controls. Speech samples were collected from a carefully described cohort of 31 adults with a history of cannabis use (but not use of illicit stimulant drugs) and 40 non-drug-using controls. Subjects completed simple and complex speech tasks including a monologue, a sustained vowel, saying the days of the week, and reading a phonetically balanced passage. Audio samples were analysed objectively using acoustic analysis for measures of timing, vocal control, and quality. Subtle differences in speech timing, vocal effort, and voice quality may exist between cannabis and control groups, however data remain equivocal. After controlling for lifetime alcohol and tobacco use and applying a false discovery rate, only spectral tilt (vocal effort and intensity) differed between groups and appeared to change in line with duration of abstinence from cannabis use. Differences between groups may reflect longer term changes to the underlying neural control of speech. Our digital analysis of speech shows there may be a signal differentiating individuals with a history of recreational cannabis use from healthy controls, in line with similar findings from gait and hand function studies.